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Companion Animals as Sentinels for Predicting Environmental Exposure Effects on Aging and Cancer Susceptibility in Humans Ruth Cooper, Carol Berkower, and Sharyl Nass, Rapporteurs National Cancer Policy Forum Forum on Aging, Disability, and Independence Board on Health Care Services Health and Medicine Division Standing Committee on the Use of Emerging Science for Environmental Health Decisions Division on Earth and Life Studies Proceedings of a Workshop
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This activity was supported by the American Kennel Club Canine Health Foundation; Animal Cancer Foundation; College of Veterinary Medicine & Biomedical Science at Texas A&M University; Environmental Protection Agency, Contract No. 68HERC19D0011 (Task Order No. 68HERC22F0077); Flint Animal Cancer Center, Colorado State University; Morris Animal Foundation; National Cancer Institute, Contract No. HHSN263201800029I (Task Order No. HHSN26300008); National Institute of Environmental Health Sciences, Contract No. HHSN263201800029I (Task Order No. 75N98020F0018); National Institute on Aging/National Institutes of Health, Contract No. HHSN2632018000029I (Task Order 75N98019F00848); Nicholas School of the Environment; North Carolina State University College of Veterinary Medicine; and University of Colorado Cancer Center. International Standard Book Number-13: 978-0-309-68794-2 International Standard Book Number-10: 0-309-68794-2 Digital Object Identifier: https://doi.org/10.17226/26547 This publication is available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2022 by the National Academy of Sciences. National Academies of Sciences, Engineering, and Medicine and National Academies Press and the graphical logos for each are all trademarks of the National Academy of Sciences. All rights reserved. Printed in the United States of America. Suggested citation: National Academies of Sciences, Engineering, and Medi- cine. 2022. Companion animals as sentinels for predicting environmental exposure effects on aging and cancer susceptibility in humans: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi. org/10.17226/26547.
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PLANNING COMMITTEE ON THE ROLE OF COMPANION ANIMALS AS SENTINELS FOR PREDICTING ENVIRONMENTAL EXPOSURE EFFECTS ON AGING AND CANCER SUSCEPTIBILITY IN HUMANS1 LINDA S. BIRNBAUM (Chair), Scientist Emeritus, National Institute of Environmental Health Sciences/National Toxicology Program; Scholar in Residence, Nicholas School of the Environment, Duke University MATTHEW BREEN, Professor of Genomics, Oscar J. Fletcher Distinguished Professor of Comparative Oncology Genetics, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University MYRTLE DAVIS, Executive Director, Discovery Toxicology, Bristol Myers Squibb NICOLE DEZIEL, Associate Professor, Yale School of Public Health, Yale Center for Perinatal, Pediatric, and Environmental Epidemiology WILLIAM FARLAND, Professor Emeritus, Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University ROY JENSEN, Director, The University of Kansas Cancer Center, Kansas Masonic Cancer Research Institute; William R. Jewell, MD Distinguished Masonic Professor, The University of Kansas Cancer Center, The University of Kansas Medical Center DANIEL PROMISLOW, Principal Investigator and Co-Director, Dog Aging Project; Professor, Department of Lab Medicine & Pathology and Department of Biology, University of Washington School of Medicine WENDY SHELTON, Principal, Virtual Beast Consulting; Consultant, Colorado State University CHERYL LYN WALKER, Alkek Presidential Chair in Environmental Health; Director, Center for Precision Environmental Health; Professor, Departments of Molecular & Cell Biology and Medicine, Baylor College of Medicine Project Staff RUTH COOPER, Associate Program Officer TOCHI OGBU-MBADIUGHA, Senior Program Assistant 1 The National Academies of Sciences, Engineering, and Medicineâs planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speak- ers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution. v
MARILEE SHELTON DAVENPORT, Senior Program Officer, Standing Committee on the Use of Emerging Science for Environmental Health Decisions (until March 2022) TRACY A. LUSTIG, Senior Program Officer; Director, Forum on Aging, Disability, and Independence SHARYL NASS, Senior Director, Board on Health Care Services; Co-Director, National Cancer Policy Forum vi
Reviewers This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in mak- ing each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings: BERNADETTE DUNHAM, George Washington University BEVERLY H. KOLLER, University of North Carolina at Chapel Hill LAUREN TREPANIER, University of WisconsinâMadison Although the reviewers listed above provided many constructive com- ments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by ELI Y. ADASHI, Brown University. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsi- bility for the final content rests entirely with the rapporteurs and the National Academies. We also thank staff member Alexandra Beatty for reading and providing helpful comments on this manuscript. vii
Acknowledgments The National Academies of Sciences, Engineering, and Medicineâs Board on Health Care Services wishes to express its sincere gratitude to the planning committee chair, Linda S. Birnbaum, for her valuable contributions to the development and orchestration of this workshop. The board also wishes to thank all the members of the planning committee, who collaborated to ensure a workshop replete with informative presentations and moderated rich discus- sions. We are also grateful for the support of our workshop sponsors, without which we could not have undertaken this project, particularly Danielle Carlin, National Institute of Environmental Health Sciences, and Rodney Page, Flint Animal Cancer Center, Colorado State University. Finally, the board wants to thank the speakers, who generously shared their expertise and their time with workshop participants. Research assistance was provided by Christopher Lao- Scott, National Academies. ix
Contents ACRONYMS AND ABBREVIATIONS xvii PROCEEDINGS OF A WORKSHOP 1 INTRODUCTION 1 BACKGROUND ON CANCER, AGING, AND ENVIRONMENTAL EXPOSURE RESEARCH 6 HISTORY AND CURRENT STATE OF THE SCIENCE OF ENVIRONMENTAL EXPOSURE EFFECTS ON AGING AND CANCER SUSCEPTIBILITY 10 Environmental Exposure and Cancer, 10 Environmental Exposure, Cancer, and Aging in Companion Animals: The Companion Dog Model, 15 Why Pet Dogs with Spontaneous Tumors are Good Models for Human Disease, 18 How Diet Modulates the Tumor Microenvironment (TME), 23 Epigenetic Aging as a Target and Biomarker for Environmental Exposures, 25 Domestic Dogs as a System for Understanding Aging and Life Span, 27 Aging, Somatic Evolution, and CancerâThe Inexorable Link, 29 Discussion: Animal Size, Reproductive Status, and Cancer, 31 METHODS AND CURRENT STUDIES 33 The Exposome and Health, 33 xi
xii CONTENTS Biomonitoring of Chemical Exposure in Companion Animals and Humans, 37 Ongoing Canine Population Studies, 40 Discussion: Advancing Use of Companion Dogs as Sentinels, 51 RELEVANCE OF COMPANION ANIMAL EXPOSURES TO HUMAN CANCER AND AGING 54 Exposures to Air Pollution, Smoking, and Lead, 54 Using Silicone Samplers to Assess Air Pollution in People and Pets, 56 Cats as Sentinels for Persistent Organic Pollutants Indoors, 58 Radon Exposures and Cancer in Pets, 61 Heavy Metal Exposures in the Dogs of Chernobyl, 62 Exposures through Food, 64 Chemical Mixtures, Cancer, and DietâThe Example of Pesticides, 65 Discussion: Relevance of Companion Animal Exposures to Humans, 68 ACCELERATING CROSS-SPECIES COMPARISONS: OPPORTUNITIES AND CHALLENGES IN DATA SOURCES, COLLECTION, STORAGE, MODELING, AND SHARING 71 Human Exposure Assessment, 71 Comparative Oncology: How Dogs are Helping Researchers Understand and Treat Cancer, 73 Biobanks for Companion Animal Sentinel Studies, 76 Using Ontologies to Unify Genomics and Phenomics across Species, 79 Data, Samples, and Modeling, 81 Discussion: Accelerating Cross-Species Comparisons, 85 EQUITY, ETHICS, AND POLICY 90 Ethical Considerations of Using Companion Animals as Sentinels: Research Subject Protections, Citizen Science Issues, and Shared Health, 90 One Health Approaches in Arctic Indigenous Communities, 93 Aligning Health Care for a Bonded Family Society, 95 Discussion: Equity, Ethics, and Policy, 96 IDENTIFYING RESEARCH GAPS AND SETTING A RESEARCH AGENDA: EXPLORING NEXT STEPS FOR THE PATH FORWARD 99
CONTENTS xiii Obtaining Data on Pets and Exposures, 99 Interdisciplinary Training of Researchers, Physicians, and Veterinarians for One Health, 100 Translating the Science between Pets and People, 101 Data Integration, 102 Data Collection: Long-Term Investment, 103 Data Collection: Tapping into Existing Cohorts (Short Term), 103 Continuing and Expanding the Conversation, 104 Community ResearchâEngagement and Equity, 104 CONCLUDING REMARKS AND POTENTIAL NEXT STEPS 105 References, 107 APPENDIXES A STATEMENT OF TASK 125 B WORKSHOP AGENDA 127 C BIOGRAPHICAL SKETCHES OF PLANNING COMMITTEE MEMBERS AND WORKSHOP SPEAKERS 133
Boxes, Figures, and Table BOXES 1 Suggestions from Individual Workshop Participants to Advance the Use of Companion Animals as Sentinels for Predicting Environmental Exposure Effects on Aging and Cancer Susceptibility in Humans, 3 2 Examples of NIEHS-Sponsored Sensor Research, 41 3 The Golden Retriever Lifetime Study, 44 4 The Dog Aging Project, 46 5 Studies of Dogs as Sentinels for Testicular Dysgenesis Syndrome, 49 FIGURES 1 Increasing incidence of common cancers and specifically colorectal cancers (CRC): Environmental etiology?, 11 2 The complexities of documenting exposures, 13 3 Dogs can serve as a useful model in comparative oncology, 17 4 The remarkable similarity in cancers that develop in humans and dogs, 18 5 The nonlinear relationship between dog age and human age, 28 6 Cancers requiring different numbers of driver mutations and originating from stem cell pools that are organized in vastly different ways demonstrate very similar age-dependent incidence, 30 7 The exposome: Implications for examining environmental health disparities, 34 xv
xvi BOXES, FIGURES, AND TABLE 8 The exposome concept, 35 9 Approaches to exposure science at the NIEHS, 40 10 Contingency Test for Trend based on (A) associations of body weight and (B) body condition scores with quartile rankings based on serum total PFAS concentrations, 60 11 The Hallmark Framework of cancer progression, 66 12 Comparative molecular features of canine and human osteosarcomas, 75 13 Development of species-agnostic ontologies to classify phenotypes across species, 80 14 Integration of exposure event modeling with the Monarch Knowledge Graph, 82 TABLE 1 A Selection of Canine Cancer Sentinel Studies Showing Positive Association or No Association with Environmental Exposure, 21
Acronyms and Abbreviations AAVSB American Association of Veterinary State Boards ACVO American College of Veterinary Ophthalmologists AD Alzheimerâs disease AI artificial intelligence AIDS acquired immunodeficiency syndrome AKC American Kennel Club AML acute myeloid leukemia ATSDR Agency for Toxic Substances and Disease Registry AVCC Access to Veterinary Care Coalition AVMA American Veterinary Medical Association BMI body mass index CA conformity assessment C-BARQ Canine Behavioral Assessment & Research Questionnaire CBPR community-based participatory research CDC Centers for Disease Control and Prevention CE continuing education CHIC Canine Health Information Center CKD chronic kidney disease CLL chronic lymphocytic leukemia CML chronic myeloid leukemia CO carbon monoxide COHA Clinical and Translational Science Award One Health Alliance xvii
xviii ACRONYMS AND ABBREVIATIONS COTC (NCI) Comparative Oncology Trials Consortium CRC colorectal cancer CRDC Cancer Research Data Commons CREID Centers for Research in Emerging Infectious Diseases CTL cytotoxic T lymphocyte CTSA clinical and translational science awards DAP Dog Aging Project DDT dichloro-diphenyl-trichloroethane DEHP di(2-ethylhexyl)phthalate DEMS Diesel Exhaust in Miners Study DOHAD Developmental Origins of Health and Disease EMR electronic medical record EMT epithelial mesenchymal transition EPA Environmental Protection Agency ER+ estrogen-receptor-positive EWAS exposome-wide association study FDA Food and Drug Administration FH feline hyperthyroidism fMRI functional magnetic resonance imaging GC gas chromatography GIS geographic information systems GO Gene Ontology GRLS Golden Retriever Lifetime Study GXE gene by environment HHEAR Human Health Exposure Analysis Resource HRMS high-resolution mass spectrometry IACUC Institutional Animal Care and Use Committee IARC World Health Organization International Agency for Research on Cancer ICDC Integrated Canine Data Commons ICP-MS inductively coupled plasma mass spectroscopy IGF insulin-like growth factor ISBER International Society for Biological and Environmental Repositories MESA Multi-Ethnic Study of Atherosclerosis
ACRONYMS AND ABBREVIATIONS xix MET mesenchymal to epithelial transition MHC major histocompatibility complex ML machine learning MOU memorandum of understanding MS mass spectrometry MWAS metabolome-wide association study NASEM National Academies of Sciences, Engineering, and Medicine NCI National Cancer Institute NGO nongovernmental organization NHANES National Health and Nutrition Examination Survey NIA National Institute on Aging NIEHS National Institute of Environmental Health Sciences NIH National Institutes of Health NIST National Institutes of Standards and Technology NSRL no-significant-risk level NTP National Toxicology Program OFA Orthopedic Foundation for Animals PATO Phenotype and Trait Ontology PBDE polybrominated diphenyl ether PBMC peripheral blood mononuclear cell PBPK physiologically based pharmacokinetics PCB polychlorinated biphenyl PDMS polydimethylsiloxane PEGS Personalized Environment and Genes Study (NIEHS) PET/CT positron emission tomographyâcomputed tomography PFAS poly- and perfluoroalkyl substances PFHxS perfluorohexane sulfonate PFOA perfluorooctanoic acid PFOS perfluorooctane sulfonic acid PHD3 prolyl-hydroxylase 3 PI principal investigator PK pharmacokinetics POC point of care device POP persistent organic pollutant PPN primary pulmonary neoplasia RACE Registry of Approved Continuing Education
xx ACRONYMS AND ABBREVIATIONS SARS severe acute respiratory syndrome SES socioeconomic status SHS secondhand smoke SNP single nucleotide polymorphism STR short tandem repeat TBT tributyltin TDCIPP tris(1,3-dichloroisopropyl)phosphate TDS testicular dysgenesis syndrome TME tumor microenvironment TRI Toxics Release Inventory program TRIAD Test of Rapamycin in Aging Dogs clinical trial TVMDL Texas A&M Veterinary Medical Diagnostic Laboratory UFP ultrafine particle VOC volatile organic compound WHICAP Washington Heights/Inwood Columbia Aging Project WHO World Health Organization